glycogen metabolism and gluconeogenesis ch 339k. glycolysis (recap) we discussed the reactions which...
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Glycogen Metabolism andGluconeogenesis
CH 339K
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Glycolysis (recap)
• We discussed the reactions which convert glucose to pyruvate:
C6H12O6 +2 NAD+ + 2 ADP 2 CH3COCOOH + 2 NADH +2 ATP + 2 H+
• What about the sources of glucose?– Dietary sugars
– Glycogen
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Before we get to glycogen: Dietary sugars
Starches
Maltose
Maltose Glucose
Sucrose
Lactose
Glucose
Fructose
Glucose
Galactose
Pancreatic Amylase
Maltase
Sucrase
Salivary Amylase
Lactase
Glucose Epimerase
Glucose Isomerase
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Amylase Reaction
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Glycogen
• Branched every 8-12 residues• Up to 50,000 or so residues total
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Breakdown: Glycogen Phosphorylase
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Glycogen Synthesis and Breakdown• Glycogen synthesis and breakdown are both
controlled by hormones• Glucagon, Epinephrine
– turn on glycogen breakdown
– Turn off glycogen synthesis
• Hormones act through receptors on cell surface and G-proteins
Glucagon – 29 amino acid polypeptide produced in pancreas in response to low blood sugar
Epinephrine – aka adrenaline – produced by adrenal medulla in response to stress
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Activation of Glycogen Phosphorylase
3’-5’ cyclic AMP
• G-Proteins• Second messengers• Kinase Cascade
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G-Proteins
G proteins are heterotrimers, containing G, G and G subunits.
Subunit Size
Ga 45 – 47 kD
G 35 kD
Gg 7-9 kD
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G-Proteins
• The G subunits bind guanine nucleotides (hence the name “G Protein”). G Proteins are associated on one hand with the inner surface of the plasma membrane, and on the other hand with membrane spanning receptor proteins called G-protein coupled receptors or GPCRs.
• There are a number of different GPCRs; most commonly these are receptors for hormones or for some type of extracellular signal.
• In the “resting” state, G is bound to the G-G dimer. G contains the nucleotide binding site, holding GDP in the inactive form, and is the “warhead” of the G protein. At least 20 different forms of Ga exist in mammalian cells.
• Binding of the extracellular signal by the GPCR causes it to undergo an intracellular conformational change; this causes an allosteric effect on G. The change in G causes it to exchange GDP for GTP. GTP activates G, causing it to dissociate from the G-G dimer. The activated G binds and activates an effector molecule.
• G also has a slow GTPase activity. Hydrolysis of GTP deactivates G, which reassociates with the G-G dimer and the GPCR to reform the resting state. In other words, G-protein mediated cellular responses have a built-in off switch to prevent them from running forever.
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G-Protein Coupled Receptors (GPCRs)
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G-Proteins – Effect of GDP/GTP Binding
GTP – terminal PO4 constrains the -binding loop (red)
GDP – missing terminal PO4 allows the -binding loop (red) to assime a looser conformation
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Cycling of G protein between active and inactive states
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G-Protein Killers
Cholera Cholera toxin secreted by the bacterium Vibrio cholera.A subunit and five B subunits. A subunit catalyzes the transfer of an ADP-ribose from NAD+ to a specific Arg side
chain of the α subunit of Gs.G is irreversibly modified by addition of ADP-ribosyl group;Modified Gα can bind GTP but cannot hydrolyze it ). As a result, there is an excessive, nonregulated rise in the intracellular cAMP level
(100 fold or more), which causes a large efflux of Na+ and water into the gut.
Pertussis (whooping cough)Pertussis toxin (secreted by Bordetella pertussis) catalyzes ADP-ribosylation of a
specific cysteine side chain on the α subunit of a G protein which inhibits adenyl cyclase and activates sodium channels.
This covalent modification prevents the subunit from interacting with receptors; as a result, locking Gα in the GDP bound form.
You probably vaccinate your dog against the related species that causes kennel cough.
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Cholera is still a problem-2009 Zimbabwe outbreak – 4300 deaths
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Activation of Adnylate Cyclase
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Activation of cAMP-Dependant Protein Kinase
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Glycogen Phosphorylase
• Exists in 2 forms– Phosphorylase B (inactive)
– Phosphorylase A (active)
• Phosphorylase B is converted to Phosphorylase A when it is itself phosphorylated by Synthase Phosphorylase Kinase (SPK)
• GP cannot remove branch points (-1,6 linkages)
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Activation of Glycogen Phosphorylase
3’-5’ cyclic AMP
cAMP – dependentProtein Kinase
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Activation of Glycogen Phosphorylase
cAMP – dependentProtein Kinase
PLP: Pyridoxal Phosphate cofactor
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Debranching Enzyme• The activity of phosphorylase ceases 4 glucose residues from the
branch point. • Debranching enzyme (also called glucan transferase) contains 2
activities: – glucotransferase – glucosidase.
• Glycogenolysis occurring in skeletal muscle could generate free glucose which could enter the blood stream.
• However, the activity of hexokinase in muscle is so high that any free glucose is immediately phosphorylated and enters the glycolytic pathway.
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Cori Disease
• Cori disease (Glycogen storage disease Type III) is characterized by accumulation of glycogen with very short outer branches, caused by a flaw in debranching enzyme.
• Deficiency in glycogen debranching activity causes hepatomegaly, ketotic hypoglycemia, hyperlipidemia, variable skeletal myopathy, cardiomyopathy and results in short stature.
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Glycogen Synthesis• Glycogen Synthase adds glucose residues to
glycogen• Synthase cannot start from scratch – needs a primer• Glycogenin starts a new glycogen chain, bound to
itself
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Glycogen Synthesis (cont.)
• Synthase then adds to the nonreducing end.
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Glycogen Synthesis (cont.)
• To add to the glycogen chain, synthase uses an activated glucose, UDP-Glucose
• UDP-Glucose Pyrophosphorylase links UDP to glucose
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Glycogen Synthesis (cont.)
• Synthase then adds the activated glucose to the growing chain
• Release and subsequent hydrolysis of pyrophosphate drives the reaction to the right
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Glycogen Synthesis (cont.)
• Glycogen branching enzyme then introduces branch points
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Mature Glycogen
• Built around glycogenin core
• Multiple non-reducing ends accessible to glycogen phosphorylase
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Reverse Regulation of Phosphorylase and Synthase
• The same kinase phosphorylates both glycogen phosphorylase and synthase
• Synthase I (dephos.) is always active
• Synthase D (phos.) is dependent on [G-6-P]
• The same event that turns one on turns the other one off.
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Gluconeogenesis
CH 339K
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Gluconeogenesis• Average adult human uses 120 g/day of
glucose, mostly in the brain (75%)– About 20g glucose in body fluids
– About 190 g stored as glycogen
– Less than 2 days worth
• In addition to eating glucose, we also make it• Mainly occurs in liver (90%) and kidneys
(10%)• Not the reverse of glycolysis• Differs at the irreversible steps in glycolysis
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Gluconeogenesis
Differs Here
And Here
And Here
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First Difference
Glycolysis: make a nucleotide triphosphate
Gluconeogenesis: burn two nucleotide triphosphates
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Pyruvate Carboxylase
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PEP Carboxykinase
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Malate Shuttle• Pyruvate Carboxylase
is mitochondrial• OAA reduced to malate
in matrix• Carrier transports
malate to cytoplasm• Cytoplasmic malate
dehydrogenase reoxidizes to OAA
• Mammals have a mitochondrial PEPCK
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Second and Third differences
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Energetics
Gluconeogenesis• Pyruvate + 4 ATP + 2 GTP + 2 NADH + 2 H2O ⇌ glucose + 4 ADP + 2 GDP + 2 NAD+
G = -37 kJ/mol
Glycolysis (reversed)• Pyruvate + 2 ATP + 2 NADH + 2 H2O ⇌ glucose + 2 ADP + 2 NAD+
G = +84 kJ/mol
Net difference of 4 nucleotide triphosphate bonds at ~31 kJ each accounts for difference in Gs
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Local Regulation
• Phosphofructokinase-1(Glycolysis) is inhibited by ATP and Citrate and stimulated by AMP.
• Fructose-1,6-bisphosphatase (Gluconeogenesis) is inhibited by AMP.
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Global Control
Enzymes relevant to these pathways that are phosphorylated by cAMP-Dependent Protein Kinase include:
• Pyruvate Kinase, a glycolysis enzyme that is inhibited when phosphorylated.
• A bi-functional enzyme that makes and degrades an allosteric regulator, fructose-2,6-bisphosphate.
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Pyruvate Kinase Regulation
• Local regulation by substrate activation• Global regulation by hormonal control of Protein Kinase A
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Effects of Fructose-2,6-Bisphosphate• Fructose-2,6-bisphosphate allosterically activates the glycolysis
enzyme Phosphofructokinase-1, promoting the relaxed state, even at relatively high [ATP]. Activity in the presence of fructose-2,6-bisphosphate is similar to that observed when [ATP] is low. Thus control by fructose-2,6-bisphosphate, whose concentration fluctuates in response to external hormonal signals, supercedes control by local conditions (ATP concentration).
• Fructose-2,6-bisphosphate instead inhibits the gluconeogenesis enzyme Fructose-1,6-bisphosphatase.
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Source of Fructose-2,6-BisphosphateFructose-2,6-bisphosphate is synthesized and degraded by a bi-
functional enzyme that includes two catalytic domains
• Phosphofructokinase-2 (PFK2) domain catalyzes:fructose-6-phosphate + ATP ⇄ fructose-2,6-bisphosphate + ADP.
• Fructose-Biosphosphatase-2 (FBPase2) domain catalyzes:fructose-2,6-bisphosphate + H2O ⇄ fructose-6-phosphate + Pi.
Phosphorylation activates FBPase2 and inhibits PFK2
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BifunctionalEnzyme
Activates PFK1
Inhibits F-1,6-bisphosphatase
Inhibits PFK1
Activates F-1,6-bisphosphatase
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Reciprocal Regulation of PFK-1 and FBPase-1
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Medical aside – nonlethal!
People with Type II diabetes have very high (~3x normal) rates of gluconeogenesis
Initial treatment is usually with metformin.
Metformin shuts down production of PEPCK and Glucose-6-phosphatase, inhibiting gluconeogenesis.
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Futile Cycles
• Occur when loss of reciprocal regulation fails twixt glycolysis and gluconeogenesis
• Anesthestics like halothane occasionally lead to runaway cycle between PFK and fructose-1,6-BPase
• Malignant Hyperthermia
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The Cori Cycle
High NADH/NAD+ Low NADH/NAD+